Pharmaceutical composition for treatment of lipid metabolism disorder

ABSTRACT

The present invention provides pharmaceutical compositions for the prevention or treatment of lipid metabolism disorders. The pharmaceutical compositions comprising, as an active ingredient, (2S)-2-benzl-3-(cis-hexahydro-2-isoindolinylcarbonyl)propionic aid (generic name: mitiglinide) or a pharmaceutically acceptable salt thereof, or a hydrate thereof exert remarkable lipid metabolism improving effect, and are useful for, for example, hyperlipidemia such as hypertriglyceridemia of diabetic patients or the like.

TECHNICAL FIELD

The present invention relates to pharmaceutical compositions for theprevention or treatment of lipid metabolism disorders which contain asan active ingredient mitiglinide having chemical structure representedby a formula (Chemical name:

-   (2S)-2-Benzyl-3-(cis-hexahydro-2-isoindolinylcarbonyl)-propionic    acid):

or pharmaceutically acceptable salts thereof, or hydrates thereof.

BACKGROUND ART

Lipid metabolism disorders are frequent complications of diabetes. Thepathological states of lipid metabolism disorders associated withdiabetes are complex. Hyperlipidemia such as hypertriglyceridemia mostlyseen in men and hypercholesterolemia mostly seen in postmenopausal womenis typical, but even in the case of normal lipidemia, qualitative changeor abnormality of serum lipoprotein is sometimes found. The lipidmetabolism disorder is a major risk factor of macrovascular disorders.Particularly, it is known that increase of triglyceride (TG), totalcholesterol (TC), low-density lipoprotein (LDL) cholesterol or remnantlipoprotein, or decrease of high-density lipoprotein (HDL) cholesterolis at high risk of advance to arteriosclerotic diseases, acutepancreatitis, coronary artery disease or the like. Therefore, it isnecessary in the treatment of diabetes to pay careful attention tocomplication such as lipid metabolism disorder like this and prevent ortreat it as well as glycemic control.

Similar lipid metabolism disorders also accompany diabetes, impairedglucose tolerance, fasting blood sugar abnormality or the like, andsometimes thyroid hypofunction, obesity, renal disorders such asnephrotic syndrome, hepatobiliary disorders, use of drugs such asadrenal cortical hormone or the like.

The frequency of hyperlipidemia in diabetes differs dependent on successand failure of glycemic control. For example, it has been reported thatthe frequency of hypertriglyceridemia is high in patients with badglycemic control. Therefore, glycemic control is also the firsttherapeutic purpose in diabetic patients with a lipid metabolismdisorder (non-Patent Reference 1). However, there are many patientswhose lipid metabolism disorders can not be solved despite good glycemiccontrol, and therefore, medication for the lipid metabolism disorder isconsidered necessary. For example, it has been reported that a singledose of nateglinide, a phenylalanine derivative, suppressed postprandialincrease of triglyceride in diabetic patient and is useful for theimprovement of postprandial hyperlipidemia (non-Patent Reference 2). Inaddition, it has been also reported that nateglinide did not show asignificant improvement on postprandial lipid variation after 12-weekrepeated administration compared to pretreatment (non-Patent Reference3). Furthermore, it has been reported that a single dose of repaglinide,a benzoic acid derivative, did not show significant improving effect onpostprandial lipid variation in diabetic patients compared to placebo(non-Patent Reference 4).

In the treatment of hyperlipidemia associated with diabetes, diettherapy, exercise therapy and lifestyle guidance are performed, and inthe case that sufficient improvement is not achieved, medication isadministered. As medication, nicotinate derivatives, HMG-CoA reductaseinhibitors, anion-exchange resins, fibrates and the like are mainly used(non-Patent Reference 5). However, these drugs can sometimes causeside-effects such as skin disorders, digestive symptoms, enhancement ofinsulin resistance, hepatic dysfunction, rhabdomyolysis, absorption ofdrug or the like, which can make it harder for a patient to continueusing the drug. Thus, a new drug which can be continuously applicablefor diabetic patients has been desired.

Mitiglinide calcium hydrate (chemical name:(2S)-2-benzyl-3-(cis-hexahydro-2-isoindolinylcarbonyl)propionic acidcalcium dihydrate) is a commercially available rapid-actingnon-sulfonylurea type antidiabetic drug represented by the followingformula (II), and is known to correct the condition such as postprandialhyperglycemic state and be useful for glycemic control in Type 2diabetic patients and the prevention or inhibition of advancing ofdiabetic complication based on the glycemic control (Patent References 1to 3). However, it has not ever been reported that mitiglinide improvesmetabolism disorders of lipids such as triglyceride, cholesterol and thelike. It has not been suggested or disclosed that mitiglinide is usefulfor the prevention or treatment of lipid metabolism disorders such ashyperlipidemia or the like in diabetic patients.

As mentioned above, it has not ever been known that mitiglinidesignificantly decreases plasma triglyceride, total cholesterol and thelike, and is useful for the prevention or treatment of lipid metabolismdisorders such as hyperlipidemia in diabetic patients as describedbelow, and that is not suggested or disclosed in the above references.

-   Patent Reference 1: Japanese Patent Publication H4-356459;-   Patent Reference 2: International Publication WO2004/002473    pamphlet;-   Patent Reference 3: International Publication WO2004/002474    pamphlet;-   Patent Reference 4: Japanese Patent Publication H6-340622;-   Patent Reference 5: Japanese Patent Publication H6-340623;-   Non-patent Reference 1: Toshiro Murase, Lipid metabolism disorder,    Nippon-Rinsho Extra supplement, Aug. 28, 2002, Vol. 60, Suppl. 8,    pp. 145-153;-   Non-patent Reference 2: Yutaka Mori, New remedies & therapy    (Shin-yaku to Chiryo), 2003, Vol. 53, No. 3, pp. 25-28;-   Non-patent Reference 3: Juha Vakkilainen, et. al.,    Diabetes/Metabolism Research and Reviews, 2002, Vol. 18, pp.    484-490;-   Non-patent Reference 4: N. Tentolouris, et. al., Exp Clin Endocrinol    Diabetes, 2003, Vol. 111, pp. 370-373;-   Non-Patent Reference 5: Joslin's Diabetes Mellitus, Igaku-shoin, pp.    385-389;-   Non-Patent Reference: Guidelines for Diagnosis of Artherosclerotic    Diseases 2002 edition, Japan atherosclerosis Society, Sep. 30, 2002,    pp. 9-17.

DISCLOSURE OF THE INVENTION Problem to be Solved by the Invention

The object of the present invention is to provide pharmaceuticalcompositions useful for the prevention or treatment of lipid metabolismdisorders such as hyperlipidemia.

Means of Solving the Problems

The present inventors have studied in detail on clinical pharmaceuticalcharacteristics of a pharmaceutical composition containing as an activeingredient mitiglinide calcium hydrate represented by the above formula(II), and found that the pharmaceutical composition has an effectremarkably lowering lipids such as plasma triglyceride, totalcholesterol, LDL cholesterol or the like, or remarkably increasing HDLcholesterol level and is extremely useful for the prevention ortreatment of lipid metabolism disorders such as hyperlipidemia or thelike, thereby forming the basis of the present invention.

The present invention relates to a pharmaceutical composition useful forthe prevention or treatment of lipid metabolism disorders such ashyperlipidemia. For more detail, the present invention relates to:

[1] a pharmaceutical composition for the prevention or treatment of alipid metabolism disorder, which comprises as an active ingredientmitiglinide represented by the above formula (I) or a pharmaceuticallyacceptable salt thereof, or a hydrate thereof;

[2] a pharmaceutical composition as described in the above [1] whereinthe lipid metabolism disorder is a disorder associated with one or moreselected from a group consisting of diabetes, impaired glucose toleranceand fasting blood sugar abnormality;

[3] a pharmaceutical composition as described in the above [2] whereinthe lipid metabolism disorder is a disorder associated with diabetes;

[4] a pharmaceutical composition as described in any one of the above[1] to [3] wherein the lipid metabolism disorder is one or more selectedfrom a group consisting of hyperlipidemia, hypertriglyceridemia,hypercholesterolemia, hyperLDL-cholesterolemia, hypoHDL-cholesterolemia,and postprandial hyperlipidemia;

[5] a pharmaceutical composition as described in any one of the above[1] to [5] wherein the active ingredient is mitiglinide calcium hydrate;and the like.

The present inventors analyzed changes in laboratory values of lipids inpatients who had a lipid metabolism disorder before the treatment wasstarted (lipid metabolism disorder group) using clinical results ofmitiglinide calcium hydrate in Type 2 diabetic patients, and evaluatedthe improving efficacy of the compound.

As a result, it was found that the present compound exerts a remarkableeffect improving the lipid metabolism disorder such as hyperlipidemia,for example, effects such as significantly lowering plasma TG, TC andLDL-cholesterol and increasing HDL-cholesterol compared to pretreatment.

The lipid metabolism disorder in the scope of the present inventionincludes the state with higher blood lipid level than normal level(hyperlipidemia), qualitative change and abnormality in bloodlipoprotein and increase of free fatty acid. In particular, ashyperlipidemia, hypercholesterolemia, hyper-LDL-cholesterolemia,hypo-HDL-cholesterolemia, hypertriglyceridemia and the like can beillustrated. As examples, a lipid metabolism disorder associated withdiabetes is preferable, and hypercholesterolemia, hypertriglyceridemiawhich are associated with diabetes are more preferable. In addition,hyperlipidemia includes postprandial hyperlipidemia.

In the present invention, the term “hyperlipidemia” basically means astate wherein total cholesterol level is 200 mg/dL or more,LDL-cholesterol level is 120 mg/dL or more, HDL-cholesterol level isless than 40 mg/dL or triglyceride level is 150 mg/dL or more, althoughthe diagnosis criteria may change according to predisposition,complications, course of disease of each patient and the like (see theabove non-Patent Reference 6).

Mitiglinide represented by the above formula (I) or a pharmaceuticallyacceptable salt thereof, or a hydrate thereof can be easily preparedaccording to method described in literature or an analogous methodthereof (for example, see the above Patent References 1, 4 and 5).

As the pharmaceutically acceptable salt of mitiglinide represented bythe above formula (I), a salt with an inorganic base such as sodiumsalt, potassium salt, calcium salt or the like, a salt with an organicamine or amino acid such as morpholine, piperidine, phenylalaninol orthe like can be illustrated. A calcium salt is preferable. In addition,as an active ingredient of the present invention, mitiglinide calciumhydrate represented by the above formula (II) is the most preferable.

When the pharmaceutical compositions of the present invention areemployed in the practical treatment, various dosage forms are useddepending on their uses. As examples of the dosage forms, powders,granules, fine granules, dry syrups, tablets, capsules, injections,solutions, ointments, suppositories, poultices and the like areillustrated, which are orally or parenterally administered.

The pharmaceutical compositions of the present invention can be preparedby suitably admixing with or by diluting and dissolving with anappropriate pharmaceutical additive pharmaceutically used depending thedosage form such as excipients, disintegrators, binders, lubricants,diluents, buffers, isotonicities, antiseptics, moistening agents,emulsifiers, dispersing agents, stabilizing agents, dissolving aids andthe like, and formulating the mixture in accordance with conventionalmethods. In the case of the uses in combination with other drug(s), theycan be prepared by formulating each active ingredient together orindividually in a similar manner as defined above.

For example, powders can be formulated by, if desired, admixing well acompound of the present invention with appropriate excipients,lubricants and the like.

For example, tablets can be easily prepared in a method described inliterature or an analogous method (see the above Patent References 2 and3). The tablets, further if desired, can be suitably coated to providefilm-coated tablets, sugar-coated tablets, enteric-coated tablets andthe like.

For example, capsules can be formulated by, if desired, admixing well acompound of the present invention with appropriate excipients,lubricants and the like and filling it in appropriate capsules.Furthermore, it is also applicable to formulate granules or fine-powdersin accordance with conventional methods, and then fill the compositionsin capsules.

Furthermore, the compounds of the present invention can be also used incombination with other hypoglycemic drugs or drugs for the treatment ofdiabetic complication. Examples of the other hypoglycemic drug which canbe used in combination with include, for example, an insulin sensitivityenhancers such as pioglitazone hydrochloride, rosiglitazone maleate orthe like, a glucose absorption inhibitor such as voglibose, acarbose,miglitol or the like, biguanides such as metformin hydrochloride,buformin hydrochloride or the like, an insulin secretion enhancer suchas tolbutamide, acetohexamide, tolazamide, glyclopyramide, glybuzole,glyburide/glibenclamide, gliclazide, glimepiride or the like, an insulinpreparation and the like. In addition, examples of the other drug forthe treatment of diabetic complications which can be used in combinationwith include, for example, an aldose reductase inhibitor such asepalrestat or the like, a sodium channel antagonist such as mexiletinehydrochloride or the like, an angiotensin converting enzyme inhibitorsuch as imidapril hydrochloride, lisinopril or the like, an angiotensinII receptor antagonist such as losartan potassium, irbesartan or thelike) and the like.

In addition, the compounds of the present invention can be also used incombination with other hypolipidemic drugs. Examples of the otherhypolipidemic drug which can be used in combination with include, forexample, a nicotinate derivative, a HMG-CoA reductase inhibitor such aspravastatin, simvastatin, atorvastatin, fluvastatin or the like, ananion-exchange resin such as colestylamine, colestimide or the like, afibrate agent such as bezafibrate, fenofibrate or the like, probucol andthe like.

In the case of uses of the compound of the present invention incombination with the above one or more other drugs, the presentinvention includes either dosage form of simultaneous administration asa single preparation or separated preparations in way of the same ordifferent administration route, and administration at different dosageintervals as separated preparations in way of the same or differentadministration route.

When the pharmaceutical compositions of the present invention areemployed in the practical treatment, the dosage of a compound of thepresent invention as the active ingredient is appropriately decideddepending on the body weight, age, sex presence or absence ofcomplication, and degree of diseases or treatment of each patient, andas a dose of mitiglinide calcium hydrate, which is approximately withinthe range of from 5 to 45 mg, preferably approximately within the rangeof from 5 to 22 mg, more preferably approximately within the range offrom 10 to 22 mg as a single dose. As an administration method,administration three times before meal is essentially preferable. Also,in the case of the uses in combination with the above other drug(s), thedosage of the compound of the present invention can be decreaseddepending on the dosage of the other drug(s).

Effect of the Invention

The pharmaceutical compositions of the present invention exert anexcellent improving effect on lipid metabolism disorders in diabeticpatients. The present invention can provide a pharmaceutical compositionuseful for the prevention or treatment of lipid metabolism disorderssuch as hyperlipidemia or the like.

BEST MODE TO PRACTICE THE INVENTION

The present invention is further illustrated in more detail by way ofthe following Example. However, the present invention is not limitedthereto.

Example 1

Clinical Efficacy on Lipid Metabolism Disorders in Diabetic Patients

The following clinical study was conducted in Type 2 diabetic patientsusing tablets containing 5 mg of mitiglinide calcium hydrate and tabletscontaining 10 mg of mitiglinide calcium hydrate.

Patients included: Type 2 diabetic patients;

Mode of dosing: oral administration of 5 to 20 mg as a single dose threetimes per day just before (5 minutes before) each meal;

Dosing period: 28 weeks to 52 weeks;

Major items of observation: stabilized hemoglobin A1c (HbA1c),biochemical examination of blood (total cholesterol, triglyceride,LDL-cholesterol, HDL-cholesterol, free fatty acid);

Statistical Method: in all patients with an abnormal value of each lipidat pretreatment and without any hypolipidemic agent, significance testwas conducted on the average of the final evaluation against the averageof the pretreatment (*: P<0.05, **: P<0.01).

(1) Changes in Serum Triglyceride (TG)

Patients with 150 mg/dL or more of serum TG at pretreatment were pickedout as an abnormal group, the efficacy of mitiglinide calcium hydratewas evaluated on the group. The result is shown in Table 1.

TABLE 1 Patients for Average of TG (mg/dL) Analysis Pretreatment Finalevaluation All patients with 262.6 216.3** 150 mg/dL or more ofpretreatment TG

(2) Changes in Serum Total Cholesterol (TC)

Patients with 200 mg/dL or more of serum TC at pretreatment were pickedout as an abnormal group, the efficacy of mitiglinide calcium hydratewas evaluated. The result is shown in Table 2.

TABLE 2 Average of TC (mg/dL) Patients for After the end of AnalysisPretreatment administration All patients with 231.8 226.4* 200 mg/dL ormore of TC

(3) Changes in Abnormal Values of Other Lipids

Patients with 0.86 mEq/L or more of serum free fatty acid (FFA), 120mg/dL or more of LDL-cholesterol (LDL-C) and less than 40 mg/dL ofHDL-cholesterol at pretreatment, respectively, were picked out asabnormal groups, the efficacy of mitiglinide calcium hydrate wasevaluated. The result is shown in Table 3.

TABLE 3 Average Patients for After the end of Analysis LipidPretreatment administration Patients with FFA 1.021 0.745** 0.86 mEq/Lor (mEq/L) more of FFA Patients with LDL-C 144.9 137.7** 120 mg/dL or(mg/dL) more of LDL-C Patients with HDL-C 34.7 40.3** less than 40(mg/dL) mg/dL of HDL-C

From patients having been enrolled in the above the above clinical studydescribed in the above Example 1, concrete examples are given asfollows.

Example 2

A 59-year-old woman. The doses were 10 mg at a time from the start ofdosing till 16th week, and increased to 20 mg after 16th week. Thevalues of TC, LDL-C and FFA at pretreatment were 240 mg/dL, 137 mg/dLand 0.94 mEq/L, respectively. At the final evaluation after 52-weekadministration, TC, LDL-C and FFA were 185 mg/dL, 108 mg/dL and 0.26mEq/L, respectively. The changes of TC, LDL-C and FFA were −55 mg/dL,−29 mg/dL and −0.68 mEq/L, respectively, and that was remarkableimprovement.

Example 3

A 54-year-old man. The dose was 10 mg through the administration period.TG at pretreatment was a high value of 171 mg/dL. At the finalevaluation after 52-week administration, TG was 110 mg/dL, the changewas −61 mg/dL, and that was a remarkable improvement.

Example 4

A 47-year-old woman. The doses were 10 mg at a time from the start ofdosing till 16th week, and increased to 20 mg after 16th week. Thevalues of TG and TC at pretreatment were 163 mg/dL and 214 mg/dL,respectively. At the final evaluation after 40-week administration, TGand TC were 101 mg/dL and 162 mg/dL, and the changes were −62 mg/dL and−52 mg/dL, respectively, and these were remarkable improvement.

Example 5

A 62-year-old man with concomitant hyperlipidemia. The doses were 10 mgat a time from the start of dosing till 16th week, and increased to 20mg after 16th week. The values of TG and FFA at pretreatment were 213mg/dL and 0.53 mEq/L, respectively. At the final evaluation after24-week administration, TG and FFA were 145 mg/dL and 0.30 mEq/L, andthe changes were −68 mg/dL and −0.23 mEq/L, respectively, and these wereremarkable improvement.

Example 6

A 37-year-old man with concomitant hyperlipidemia. The dose was 10 mgthrough the administration period. The values of TC and LDL-C atpretreatment were 260 mg/dL and 149 mg/dL, respectively. At the finalevaluation after 52-week administration, TC and LDL-C were 203 mg/dL and134 mg/dL, and the changes were −57 mg/dL and −15 mg/dL, respectively,and these were remarkable improvement.

Example 7

A 64-year-old woman. The dose was 10 mg through the administrationperiod. The values of TG, TC, LDL-C and HDL-C at pretreatment were 170mg/dL, 226 mg/dL, 129 mg/dL and 57 mg/dL, respectively. At the finalevaluation after 52-week administration, TG, TC, LDL-C and HDL-C were100 mg/dL, 206 mg/dL, 116 mg/dL and 72 mg/dL, and the changes were −70mg/dL, −20 mg/dL, −13 mg/dL and +15 mg/dL, and these were remarkableimprovement.

As mentioned above, it was shown that in the clinical study usingmitiglinide calcium hydrate for diabetic patients, the compound of thepresent invention exerts remarkable effects to lower TG, TC, LDL-C orFFA, or increase HDL-C in patients with high blood TG, blood TC, FFA orLDL-C, or low HDL-C.

INDUSTRIAL APPLICABILITY

The pharmaceutical compositions of the present invention exert effectsto suppress the increase of lipids such as serum TG, TC, LDL-C and thelike or increase HDL-C, and are extremely useful as an agent for theprevention or treatment of lipid metabolism disorders such ashyperlipidemia or the like.

1. A method for the treatment of a lipid metabolism disorder wherein thelipid metabolism disorder is hyperlipidemia, which consists essentiallyof administering a therapeutically effective amount of mitiglinide or apharmaceutically acceptable salt thereof, or the calcium hydratethereof.
 2. A method for the treatment claimed in claim 1 wherein thelipid metabolism disorder is a disorder associated with one or moreselected from a group consisting of type II diabetes, impaired glucosetolerance and fasting blood sugar abnormality.
 3. A method for thetreatment claimed in claim 2 wherein the lipid metabolism disorder is adisorder associated with type II diabetes.
 4. A method for the treatmentclaimed in any one of claims 1 to 3 wherein the lipid metabolismdisorder is one or more selected from a group consisting ofhypertriglyceridemia, hypercholesterolemia, hyperLDL-cholesterolemia andhypoHDL-cholesterolemia.
 5. A method for the treatment claimed in claim4, which consists essentially of administrating a therapeuticallyeffective amount of mitiglinide calcium hydrate.
 6. A method for thetreatment claimed in claim 5, which consists essentially of orallyadministering 10 to 22 mg three times daily of mitiglinide calciumhydrate.
 7. A method for the treatment claimed in claim 5, whichcomprises administering for 6 months or more.
 8. A method for thetreatment claimed in claim 6, which comprises administering for 6 monthsor more.